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Mesenchymal Stem/Stromal Cells Increase Cardiac MIR-187-3P Expression in Polymicrobial Animal Model of Sepsis
Author(s) -
Amin M. Ektesabi,
Keisuke Mori,
James N. Tsoporis,
Chirag M. Vaswani,
Sahil Gupta,
C.T. Walsh,
Amir K. Varkouhi,
Shirley H. J. Mei,
Duncan J. Stewart,
W. Conrad Liles,
John C. Marshall,
Pingzhao Hu,
Thomas G. Parker,
Claudia C Dos Santos
Publication year - 2020
Publication title -
shock
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.095
H-Index - 117
eISSN - 1540-0514
pISSN - 1073-2322
DOI - 10.1097/shk.0000000000001701
Subject(s) - sepsis , mesenchymal stem cell , microrna , transcriptome , medicine , downregulation and upregulation , stem cell , stromal cell , gene expression profiling , gene expression , immunology , cancer research , biology , gene , pathology , microbiology and biotechnology , genetics
Sepsis-induced myocardial dysfunction (MD) is an important pathophysiological feature of multiorgan failure caused by a dysregulated host response to infection. Patients with MD continue to be managed in intensive care units with limited understanding of the molecular mechanisms controlling disease pathogenesis. Emerging evidences support the use of mesenchymal stem/stromal cell (MSC) therapy for treating critically ill septic patients. Combining this with the known role that microRNAs (miRNAs) play in reversing sepsis-induced myocardial-dysfunction, this study sought to investigate how MSC administration alters miRNA expression in the heart. Mice were randomized to experimental polymicrobial sepsis induced by cecal ligation and puncture (CLP) or sham surgery, treated with either MSCs (2.5 × 105) or placebo (saline). Twenty-eight hours post-intervention, RNA was collected from whole hearts for transcriptomic and microRNA profiling. The top microRNAs differentially regulated in hearts by CLP and MSC administration were used to generate a putative mRNA-miRNA interaction network. Key genes, termed hub genes, within the network were then identified and further validated in vivo. Network analysis and RT-qPCR revealed that septic hearts treated with MSCs resulted in upregulation of five miRNAs, including miR-187, and decrease in three top hit putative hub genes (Itpkc, Lrrc59, and Tbl1xr1). Functionally, MSC administration decreased inflammatory and apoptotic pathways, while increasing cardiac-specific structural and functional, gene expression. Taken together, our data suggest that MSC administration regulates host-derived miRNAs production to protect cardiomyocytes from sepsis-induced MD.

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